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Ann Thorac Surg 2000;70:575-581
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Neurological evaluation and intelligence testing in the child with operated congenital heart disease

^a Departments of Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
^b Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
^c Department of Pediatric Psychology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
^d Department of Cardiac Anaesthesia, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

Address reprint requests to Dr Sharma, Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India
e-mail: rsharmacvs{at}hotmail.com

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. The immediate and intermediate-term neurodevelopmental outcome in infants undergoing open heart procedures using deep hypothermic cardiopulmonary bypass was assessed prospectively.

Methods. One hundred consecutive infants (age 2 to 174 days) were operated on using either deep hypothermic bypass only (group A, n = 28), or with associated circulatory arrest (group B, n = 72). Early neurological outcome was recorded. Survivors underwent mental development evaluation after 31 to 55 months. Fifty other children of similar demographic profile but without heart disease were also tested as controls.

Results. In group A, there were two neurological deaths. In group B, 5 patients had clinical seizures, 1 had monoparesis and 1 had hyperkinetic syndrome with decreased attention span. Mean mental performance quotient was 90.0 ± 8.2 in group A, and 89.1 ± 6.8 in group B, (group A vs. B, p = 0.60). Mean mental performance quotient in the control group was 101.4 ± 8.4, which was significantly higher than the patient population (p 0.001). No correlation was found between duration of circulatory arrest and postoperative mental performance quotient.

Conclusions. There was significant retardation of mental development in infants operated with deep hypothermic cardiopulmonary bypass. However, use of total circulatory arrest and its duration did not affect clinical outcome up to preschool age.

	Introduction

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Cerebral dysfunction is a major cause of mortality and morbidity after repair of congenital cardiac defects in the young child [1–4]. Clinical and experimental data elucidating the various factors supposed to participate in neurologic injury continue to accumulate [5–11]. Yet, the optimum strategy for cerebral preservation during repair of complex congenital heart disease in the neonate and infant still remains to be defined. Subtle brain damage is especially difficult to pick up in the newborn child and the final outcome can only be realized after neurodevelopmental testing in the school-going age group. We present the midterm results of neurological and intelligence testing in infants operated upon using deep hypothermic cardiopulmonary bypass (CPB) at our center.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Patients
One hundred consecutive infants, age range 2 days to 6 months (mean 74 days), who underwent intracardiac repair of congenital heart defects by the same surgical and anesthetic team between January 1994 and December 1995 under deep hypothermia, form the substrate for this prospective study. One patient with preoperative seizures resulting from a cardiac arrest and 2 with trisomy 21 were excluded from the study. Weight ranged from 2.2 to 4.5 kg with a mean of 3.1 kg.

Anesthetic management
No premedication was administered. An intravenous infusion of 10% dextrose was begun upon arrival in the operating room. Ketamine was given in a dose of 2 mg/kg intravenously. Muscle relaxation was obtained using intravenous vecuronium in a dose of 0.15 mg/kg for intubation. Anesthesia was maintained with incremental doses of morphine (0.5 to 1-mg doses up to a maximum total dose of 2 mg/kg) and inhalational anesthetic agents (halothane/isoflurane). Additional pancuronium was given in doses of 0.5 mg every half hour for maintenance of muscle relaxation. Other drugs administered were heparin in a dose of 4 mg/kg before, and phenoxybenzamine 1 mg/kg after, aortic cannulation. Thiopentone 10 mg/kg was given 5 minutes before circulatory arrest in all patients in group B. Blood glucose levels were estimated soon after going on bypass and after commencement of rewarming. Blood glucose was maintained at 100 to 150 mg% for the duration of extracorporeal support. Insulin infusion was used as required.

Cardiopulmonary bypass management
Operating room temperature was maintained at 22°C and the thermoregulatory blanket was also set at the same level to provide surface cooling during anesthesia induction. Subsequently, if circulatory arrest was planned, an ice cap was applied to the head and the blanket temperature lowered to 4°C. CPB was established with aortic and single right atrial or bivenous cannulation. Nonpulsatile flow was maintained using a roller pump and a membrane oxygenator. A 40-µm arterial filter was used as a routine. Prime volume was 600 mL, of which, 500 mL was made up by fresh citrated whole blood and the rest of Ringer’s lactate. Mannitol (20%, 5 mL/kg) and methyprednisolone (30 mg/kg) were also added to the prime. Hematocrit was kept at approximately 30% for the entire duration of CPB. Core cooling was initiated by lowering the bath temperature to 4°C over a 5-minute period and cooling continued until nasopharyngeal temperature (Tnp) and rectal temperature (Trect) reached desired deep hypothermic levels. Blood gas management during CPB was directed at maintaining a pH of 7.35 to 7.40 with a pCO₂ of 35 to 40 mm Hg, uncorrected for body temperature (-stat). Initial pump flows were 120 to 150 mL/kg/min. In operations where only single atrial cannulation was used for venous return, pump flows were reduced to one-half to two-thirds of normal flow after aortic clamping to facilitate at least part of the repair while still maintaining systemic perfusion. Total circulatory arrest was instituted for all aortic arch repairs and wherever continuation of the operation was not possible on CPB. If a prolonged circulatory arrest period was anticipated, it was broken into a series of smaller arrest times of 30 minutes’ duration with intervening hypothermic bypass stretches (flow rate 100 mL/kg/min) of 10 minutes each. Core rewarming was always done gradually, not allowing the bath temperature to exceed body temperature by 5°C and not permitting a gradient of more than 3°C between Tnp and Trect. Separation from CPB was achieved once a Tnp of 37°C and a Trect of 34°C was reached.

Recovery period
Patients were kept paralyzed and sedated for the first 24 to 48 hours after surgery. After this time period, if hemodynamics were stable and accompanied by satisfactory diuresis, neuromuscular blockade was discontinued. Any clinically obvious seizures or abnormal movements were noted. Extubation and weaning from inotropes were done as indicated by the patient’s status. A neurological consultation and a computerized axial tomographic (CAT) scan of the brain were obtained in case of any neurological abnormality.

Follow-up in the outpatient clinic
All survivors were followed up in the outpatient clinic. Cardiac status was evaluated on each follow-up visit, which were at intervals of, initially, 3 months, then 6 monthly, and, subsequently, yearly. At all these visits, a record of the child’s physical and developmental milestones was kept, and parents were questioned regarding occurrence of any seizures. Additionally, all survivors of the study group were asked to report for neuropsychiatric evaluation in the period from May 1997 up to December 1998.

Neurological evaluation
One of two pediatric neurologists examined all the children in the period ranging from May to December 1998. Neurologists were blinded to the nature of cardiac surgery and CPB strategy used during the surgery. Only those patients considered by the neurologist to require further evaluation were subjected to magnetic resonance imaging (MRI) in the follow-up period.

Mental performance evaluation
A pediatric psychologist blinded to the nature of surgery and CPB evaluated all the patients reporting for follow-up in the time period between May and December 1998. The youngest child was 36 months old and the oldest 5 years old at this evaluation. Because of the lack of any systematic cross-sectional study on intelligence development in children in the Indian subcontinent, a group of 50 similar age- and gender-matched children presenting to the outpatient clinic of the hospital for nonneurological/noncardiac complaints was also tested in an identical manner to serve as control.

A revised version of Gessell’s development schedule (All India Institute of Medical Sciences [AIIMS] version) [12, 13] was used. It was the equivalent of the Bayley scale of infant development [14] and the McCarthy scale of childhood abilities [15]. The items for testing included in the AIIMS version have been taken from the Indian studies conducted by Phatak for children aged between 1 and 30 months and the Indian Council for Education Research and Training’s adaptation of Gesell’s developmental schedule for older children [16–18]. The system of scoring used in this version has been evolved for studying longitudinal mental development covering motor, adaptive, language, and social aspects of development, and yields a comprehensive mental developmental score. From this score, mental age can be found by referring to a chart designed for this study [12]. Mental Performance Quotient (MPQ) is then derived using the formula: mental age/chronological age x 100.

Statistical analysis
Continuous and interval-related variables were expressed as mean ± standard deviation. Preoperative continuous and interval related variables were compared using a Student’s t test. Postoperative outcome (MPQ) was compared using one-way analysis of variance (ANOVA) with multiple range test. The outcome in the strategy consisting of low-flow bypass only (group A) was compared with the strategy consisting of a period of total circulatory arrest (group B). Outcome in groups A and B was also compared with results obtained in controls. Secondary analysis examined the effect of the duration (in minutes) of circulatory arrest on outcome. To compare other postoperative outcomes, either a Student’s t test or Fischer’s exact test, wherever applicable, was used.

	Results

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The diagnoses and operative procedures are listed in Table 1.

Preoperative and intraoperative variables of both groups are shown in Tables 2 and 3.

Neurological outcome
Neurological outcome is summarized in Table 4.

Neurological workup
Survivors of group A are free from neurological deficits. In group B, 1 child has nystagmus related to a visual defect. Another child has weakness of one lower extremity and exaggerated deep tendon reflexes on that side. A third patient is hyperkinetic with decreased attention span but has no localizing motor or sensory deficit on neurological examination.

CAT scans in the early postoperative period were obtained in 7 infants, 2 of which were for pupillary inequality and other evidence of severe neurological abnormality on days 3 and 4 after surgery. One showed extensive infarction of the right cerebral hemisphere and the other generalized cerebral edema with obliteration of the ventricles. Both the infants expired. The other five scans were done in patients who had clinical seizures after surgery. These were read as normal.

MRI scan was obtained in 7 children on follow-up. The indications were recent or past history of seizures (n = 5), nystagmus (n = 1), and monoparesis (left lower limb) with exaggerated deep tendon reflexes on that side (n = 1). In 6 patients, MRI scan was normal. In the patient with monoparesis, it showed a small cortical infarction on the contralateral side.

Mental performance quotient (MPQ)
Mean MPQ and its range in operative survivors and controls is shown in Figure 1. The mean MPQ in patients operated without circulatory arrest (group A) was 90.0 ± 8.2 (range 70 to 106) and in patients with circulatory arrest was 89.1 ± 6.8 (range 74 to 110). The mean MPQ in the entire patient group was 89.3 ± 7.2 (range 70 to 110), compared with 101.4 ± 8.4 (range 88 to 120) in the control group. There was no significant difference in results of mental performance evaluation of patients in different groups (group A vs. B, p > 0.05). However, when compared with controls, operated patients had significantly lower MPQ: control vs. group A, p 0.001), control vs. group B, p 0.001 and control vs. group A + B, p 0.001. The length of arrest time was analyzed in relation to the patient’s MPQ score. No correlation was found between duration of circulatory arrest and postoperative MPQ score (p = 0.63).

View larger version (21K): [in this window] [in a new window]   Fig 1. Mean MPQ in different groups. Brackets indicate SD.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
Controversy surrounds the safety of deep hypothermic circulatory arrest as a support strategy during repair of complex congenital heart disease [3, 4, 11]. More specifically, as the duration of circulatory arrest exceeds 30 minutes at 20°C, risk of significant neurological damage is said to increase [1, 11]. The present study is somewhat at variance with this conclusion. Because, in spite of circulatory arrest times of more than 30 minutes in 28 of the 92 infants in the study, the neurological outcome and intelligence quotient in these children were not statistically different from those infants treated with either shorter periods of circulatory arrest or no circulatory arrest. The factors responsible for this perceived lack of aggravation of cerebral dysfunction with prolongation of circulatory arrest period in this series could be multiple, and are discussed below.

Prolonged cooling period before institution of circulatory arrest
The shortest mean time on deep hypothermic bypass before circulatory arrest for any of the four groups using circulatory arrest was 38 minutes. In most previously published data, much shorter cooling times have been used [19]. One study in particular [20] clearly proves that in some patients jugular bulb venous saturation even after reaching profoundly hypothermic temperatures continues to be unacceptably low, thereby implying continuing cerebral metabolism. Because it is cumbersome to insert a catheter into the jugular bulb of all small infants who might need circulatory arrest as part of their management strategy, we have been arbitrarily using an extended period of prearrest cooling to ensure uniform and adequate cerebral cooling. The disadvantages attendant upon a longer bypass period vis a vis brain protection ie, greater chance of cerebral embolization, clearly seem to be surpassed by the advantage of superior cooling.

Lower deep hypothermic temperatures than have usually been used
In any patient where a substantial portion of the surgical procedure had to be accomplished on circulatory arrest (groups B2, B3, B4), cooling to 15°C to 18°C was used. A number of groups are now practicing TCA at these very low temperatures [1]. In our opinion, an extended cooling with cooling to lower temperatures may possibly be the critical factor for achieving uniform cerebral cooling.

Breaking up a prolonged TCA period into a series of smaller arrest times
With intervening hypothermic bypass stretches this may prevent the deleterious effects of a single protracted arrest period [21, 22]. This modification was effected whenever a protracted period of circulatory arrest was anticipated. All patients included in group B4 had a TCA period split into two or more portions in the above fashion.

Normoglycemia
The literature is replete with the deleterious effects of hyperglycemia in the setting of cardiac arrest with respect to recovery of cerebral function [23, 24]. From a teleogical point of view, however, it would stand to reason that an outcome (elevation of blood glucose) that is a result of a stress response (hormonal) mounted by the body would have the function of preserving the organ systems of prime importance to the body, ie, heart and brain. Data are now forthcoming regarding the importance of glucose in the reperfusion period in recovery of biochemical integrity of ischemic neurons [25]. Traditionally, blood sugar levels have been maintained above 100 mg/L during CPB in pediatric perfusions at our center.

Hematocrit
Hemodilution down to 20% to 25% at deep hypothermia has been the rule in most pediatric perfusion protocols. The rationale has been to avoid hyperviscosity secondary to hypothermia and resultant inadequate organ perfusion. The deleterious effect of hemodilution is reduced oxygen-carrying capacity of the blood and a tendency for fluid of low oncotic pressure to accumulate in the extravascular space. As retained extracellular fluid is a well-known cause of morbidity in the postoperative period, our protocol has been to use a predominantly blood prime in infant perfusions and to keep the hematocrit at 30%. Support for such a high hematocrit prime as regards cerebral perservation has also been obtained from recent experimental studies [26, 27].

Alpha stat pH strategy
This was used for this study group. This is contrary to the present day belief that a more acidic pH stat strategy provides for luxuriant cerebral blood flow and therefore superior cerebral cooling [7, 28]. A pH stat strategy is preferable if a short period of prearrest cooling is used. An alpha stat strategy is probably better for a prolonged cooling phase to avoid the problem of microembolization and cerebral hyperemia related to an increased CPB duration [28, 29].

Adequate and uniform cerebral hypothermia is known to be neuroprotective. Thus, no cerebral events were noticeable in 83 of 94 patients in the study (six nonneurological deaths excluded for want of follow-up). However, the presence of neurologic injury in the patients irrespective of CPB strategy (2 of 27 in group A and 7 of 67 in group B) and of depressed mental performance in the entire group is remarkable. For all intents and purposes, periods of circulatory arrest as experienced by group B1 (ie, a mean arrest period of 6.8 ± 1.4 minutes) did not make that group any different than group A (ie, no circulatory arrest) at the temperatures prevalent at that time (ie, 18°C to 20°C) [30]. The observation of severe brain damage in 2 patients who were not subjected to any period of circulatory arrest and of clinical seizures and other neurological abnormalities in group B1 are, therefore, probably manifestations of the drawbacks of hypothermic CPB as applied to the small infant. Both the expired patients had satisfactory arterial line pressures during bypass, with unobstructed venous drainage, and the conduct of CPB was no different from any of the other patients managed without TCA. These cases highlight the possibility of unsuspected cerebral malperfusion, either diffuse or localized, occurring in the most unlikely circumstances. Here, middle cerebral artery blood flow velocity and cerebral oximetry may help in timely detection of hypo- or hyperperfusion or inadequate venous drainage from various parts of brain, and thus may help in initiating timely corrective action [31, 32].

A striking finding in this report was the lower MPQ in the patients who had been subjected to repair for their heart defects as compared with the control group. Although we did not study MPQ in a comparable cohort with uncorrected heart disease (to exclude the possibility of heart disease associated with a secondary effect on mental performance), it does seem likely that the mild (yet significant) retardation may have resulted from the pre-, intra-, and postoperative manipulations that the child went through while his heart defect was being repaired.

Seizures occuring early after surgery were one of the earliest indicators of cerebral injury. One of the drawbacks of this study is that only clinically evident seizure activity could be noted, as continuous electroencephalogram monitoring was not used for the duration when the infant was kept paralyzed and sedated immediately after surgery.

The results obtained in this study group indicate, therefore, that no presently available method of support strategy is perfect and, therefore, argues against any complacency that a technique of continued CPB may breed. For this reason, a rapidly achieved accurate repair with a period of planned circulatory arrest may be superior to a technically difficult and slower repair performed with continued CPB.

Heterogenous congenital lesions, the possibility of preexistent but undiagnosed cerebral lesions, different ages at operation, and different ages at follow-up are some of the drawbacks that have not been addressed in this evaluation. In addition, no allowance has been made for the socioeconomic and educational background of the families to which these children belong. The possibility of an upbringing without exposure to normal social stimuli as a parental protective behavior having ramification on a slower intellect cannot entirely be excluded in the child operated on for heart disease. If this is true, further follow-up studies should show this group merging into the normal population with increased follow-up. Also, because of the as yet small age of the children being followed, expressive and receptive language could not be uniformly tested. It will be of interest to see whether any of these groups of children with so far demonstrably equal, though less than normal, intelligence fares differently from others once scholastic performance and social interaction start occupying center stage.

	Acknowledgments

 
We thank Rajvir Singh, MSc (Stat) for statistical analysis.

	References

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